So You Want To Develop A Product for A Rare Disease…Orphan Drug Development Considerations in Today’s Regulatory Environment

January 4, 1983, was a key date in history for the pharmaceutical industry: President Ronald Reagan signed into law the Orphan Drug Act which encourages the development of drugs and biologics for rare diseases and conditions.  21 CFR 316 Subpart B provides FDA’s interpretation of the law to be applicable to:
·       Drugs intended for diseases or conditions affecting 200,000 or fewer people in the United States
·       Vaccines, diagnostic drugs, or preventive drugs that would be given to 200,000 or more persons per year when there is no reasonable expectation that the costs of drug development and marketing will be recovered over the course of 7 years following approval of the drug in the United States.[1]
There has been a fairly steady increase in orphan drug designations since 1983 (see Figure 1), and an explosion of designation applications submitted and designations granted since 2004.  2013 was a record-breaking year: there were 260 designations granted out of a total of 346 designations requested.

Figure 1: Number of US Orphan Drug Designation Applications, Designations, and Approved Orphan Products by Year[2]


A skeptic might argue that this increase is the result of more activity in general in the pharmaceutical sector and a greater number of submissions to FDA overall.  By way of comparison, looking only at new molecular entities (NMEs) filed to CDER and approvals in the last decade, this doesn’t seem to be the case (Figure 2).  NME submissions have held relatively constant over the last decade.

Figure 2
: Number of US NME Applications Submitted to and Approved by CDER by Year[3]


Together, these data support what most in pharma think they already know about industry trends:  There has been a significant shift to developing more drugs and biologics for orphan indications than ever before.  The increase in orphan drug development is easy to understand because the benefits of orphan drug development are well known and have been discussed widely by both FDA and industry[4],[5]:

·       Waiver of User Fees for drug and biologics new drug applications
·       7 years of marketing exclusivity upon approval of the orphan indication
·       50% tax credit for clinical research and testing expenses (although few companies take advantage of this)
·       Eligibility for specific orphan drug development grants through FDA’s Office of Orphan Products Development (even fewer companies take advantage of this!)
·       Increased flexibility by the Agency to use scientific judgment during the development and review of orphan products.  This is often interpreted as a more streamlined drug/biologic development pathway with fewer and/or smaller clinical trials than therapies for non-orphan indications.[6]
If we think about the dramatic increase in orphan drug designation requests and designation approvals in the last 10 years as more “shots on goal” for regulatory approvals, it is incredibly surprising that the actual number of orphan drug approvals has not also increased dramatically.  Looking at Figure 1 (red bars), it is clear that orphan drug approvals have been relatively steady since 1996.

The big question is WHY???

In a nutshell, orphan drug development comes with special and unique (some might argue, hidden) challenges that are likely to slow development and can interfere with successful product approval.[7]  For example, the study of rare disease indications can pose a myriad of logistical headaches in the clinic.
·       There are fewer patients with the disease of interest and recruitment can be challenging.  Sponsors may encounter fierce competition for patients if multiple companies are pursuing development in the same patient population.  In some cases, clinical protocols rule out the use of other investigational products, making some patients ineligible to participate in more than one clinical trial, thereby further reducing the eligible patient population for study.
·       Patients and caregivers may need to travel great distances to participate in clinical studies.
·       There may be few physicians who are experts in the orphan disease and educational efforts to diagnose and treat patients under a clinical protocol may be necessary.
There are often regulatory hurdles as well.  While typically touted as an advantage, health authorities have the flexibility to exercise judgment when reviewing and approving products to treat orphan indications and consequently the regulatory pathway can be unclear.4  For example,
·       Selection of efficacy outcome measures that are sensible from a treatment and standard of care perspective that also satisfy regulators can be particularly challenging for rare diseases.  Sometimes this means establishing brand new outcome measures and preparing full validation packages for those measures.  A recent example of this situation is described in the advisory committee meeting background materials for Otsuka’s drug tolvaptan for the treatment of autosomal dominant polycystic kidney disease (see
·       For any given product being developed for a rare disease, what is the required amount of efficacy data needed to demonstrate a therapeutic effect?  What is the required amount of exposure to demonstrate that the product is safe?  How many studies are required?  What is the right trial design?  The answers to these questions have proven to be disease- indication- and product-specific.
·       There may be few, if any, regulators who are experts in the disease indication.  Educational efforts may be necessary to bring health authorities up to speed on the disease state, what factors are important to patients in the treatment of the disease, and possibly varying benefit/risk assessments between patients, physicians and regulators.
Knowing about the challenges of orphan product development and proper planning can make all the difference.  Some of the challenges in the clinic can be overcome by working with key opinion leaders in the area, recruiting globally, providing educational outreach programs to obtain patients and caregivers, and aggressive advertising and reimbursement for clinical trial participation.

Similarly, challenges in the regulatory arena can be managed by early and frequent discussions with regulators to educate and establish a defensible, streamlined development program that will lead to successful registration.  In some cases, orphan drug development may actually take LONGER and COST MORE than non-orphan indications.  Sponsors need to be prepared for this possibility and working with regulatory strategists with specialized experience in orphan drug development can improve your probability of success.  Not only have experienced strategists formed critical relationships with health authority orphan drug evaluators, but they have “been there, done that” and understand most clearly how risk and benefit are weighed by regulators.

What is certain is that those who embark on the rare disease market must carefully weigh the pros and cons, particularly when the product in question is the only product in the Sponsor’s portfolio.  Ultimately, careful planning, a flexible and creative mindset, experienced orphan drug regulatory strategists on your side, and an “eyes wide open” approach is likely to be the difference that gets your shot in the proverbial goal.

[1] Thomas M. The Orphan Drug Act and the Development of Products for Rare Diseases.  Accessed 16 May 2014.
[2] Karst K. The Numbers Are In! 2013 Was An Across-the-Board Record Breaker for Orphan Drugs.  FDA Law Blog.  20 Mar 2014.  Accessed 16 May 2014.
[3] CDER Novel New Drug Summary 2013.  January 2014.  Accessed 16 May 2014.
[4] Needleman K. Rare Diseases and FDA:  Perspectives from the Office of Orphan Products Development (OOPD).  IRDiRC conference, April 16-17, 2013.
[5] Meekings KN, Williams CSM, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D.  Drug Development Today. 2012;7:660-4.
[6] Sasinowski FJ.  Quantum of effectiveness evidence in FDA’s approval of orphan drugs.  National Organization for Rare Disorders (NORD).  2011.
[7] Sharma A, Jacob A, Tandon M, Kumar D.  Orphan drugs: Development trends and strategies.  J Pharm Bioallied Sci. 2010;2(4):290-9.